Targeted lymphatic transport and modified systemic distribution of CI-976, a lipophilic lipid-regulator drug, via a formulation approach

Abstract

CI-976 is a poorly water soluble lipid regulator with good solubility in triglycerides and a high octanol:water partition coefficient. These physicochemieal properties suggest significant lymphatic transport following gastroin-testinal absorption. Studies were conducted to assess the relative contribution of lymphatic transport to total systemic bioavailability. Following intraduodenal administration to conscious rats as either a 20% o/w emulsion prepared from a mixture of soybean and safflower oils, or as an aqucous suspension, the percentage contribution of lymphatic transport to bioavailability as reflected by CI-976 plasma AUC was 43% for the emulsion and 57% for the suspension. However, the total quantity of CI-976 transported in lymph over 14 h,as a percent of dose administered, was 7-times greater for the emulsion as compared to the suspension. Tissue distribution studies using [14C]CI-976 showed that, compared to the suspension, the emulsion delivery system resulted in 43% greater accumulation of intact CI-976 in the perirenal fat. Enhanced lymphatic transport is not necessarily reflected by a proportionally elevated plasma AUC therefore plasma AUC, alone may not be representative of total systemic bioavailability of drug.